Lyme disease is a significant threat to human health throughout many parts of the USA. The causative agent, Borrelia burgdorferi, is maintained in nature by infectious cycles involving ticks and many species of vertebrates, with humans being incidental hosts. Understanding the mechanisms by which B. burgdorferi infects humans and is transmitted from vector ticks will be important in development of improved methodologies to prevent and treat this disease. During transmission from tick to mammal, 6. burgdorferi significantly increases expression levels of the Erp family of outer surface proteins. Expression of Erp proteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferi encode multiple Erp lipoproteins, a ubiquity that is highly suggestive of important roles for these proteins in B. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulator factor H in vitro, raising the possibility that these proteins may function in vivo to protect the bacteria from killing by the host's innate immune system. Based on results of our previous studies, we hypothesize that Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processes, and that these functions necessitate the bacteria regulate Erp expression. To test this hypothesiswe will (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erp mutants for their abilities to bind factor H, resist complement-mediated killing, and infect mice and ticks; (2) examine mechanisms by which B. burgdorferi controls Erp expression, including innovative analyses of transcription throughout mammalian and tick infection; and (3) characterize functions of the novelDMA binding proteins we discovered that specifically bind to erp operator DMA. Results of our studies will provide important insight into the mechanisms by which B. burgdorferi infects humans.